1. Field of the Invention
The present invention relates to a pyrrolidin-3-ylacetic acid derivative. More particularly, the present invention relates to a pyrrolidin-3-ylacetic acid derivative having availability as a therapeutic agent for inflammatory bowel disease.
2. Related Background Art
Chemokines are major cell migration factors and regulate infiltration of lymphocytes into tissues through the enhancement of cell movement and the activation of adhesion molecules. Chemokines are classified into four subfamilies of CC, CXC, C and CX3C based on their sequences of the first two cysteine residues.
Fractalkine is the sole CX3C chemokine member and has distinct characteristics in its structure and functions which are not found in other chemokines. Fractalkine binds to a receptor, CX3CR1, which can mediate strong adhesion without mediation of selectin or integrin even in the presence of a physiological blood flow. This means that the fractalkine-CX3CR1 system mediates multi-stage infiltration mechanism through selectin or integrin by only a one-stage reaction.
Expression of fractalkine on vascular endothelial cells is induced by inflammatory cytokines TNF and IL-1. On the other hand, CX3CR1 is expressed on monocytes, almost all NK cells and some T cells, but is not expressed on neutrophils. Therefore, the fractalkine-CX3CR1 system is considered to be an extremely effective mechanism to mobilize immune cells onto the endothelial cells of damaged tissues or into the tissues.
With regard to the relation between the fractalkine-CX3CR1 system and pathologies, it is suggested that the fractalkine-CX3CR1 system is involved in the development and pathologies of autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, lupus nephritis and multiple sclerosis (Non Patent Literature 1). In particular, with regard to inflammatory bowel disease, it is reported that expression of fractalkine is enhanced at inflammatory sites of colonic tissues of patients and that CX3CR1 plays an important role in the infiltration of immune cells into the colon tissue (Non Patent Literature 2).
Antibodies described in Patent Literature 1 and low molecular weight compounds described in Patent Literatures 2 to 6 have been previously known as fractalkine inhibitors.
In addition, compounds described in Patent Literature 7 are described to be useful as chemokine CCR2 receptor antagonists, but differ in the target chemokine family from such inhibitors.